The progression from myocardial hypertrophy to heart disease and ultimately to heart failure is a complex, multifactorial process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart disease has been difficult, largely due to the genetic heterogeneity of human populations. The goal of this project is to identify candidate genes and functional polymorphisms {SNPs) in the mouse and to determine if SNPs in the human orthologs of the candidate genes affect the progression of heart disease. The following specific aims will be addressed in this proposal: (1) Fine map the region of Hrtfm4 (a previously identified QTL affecting cardiac function and mortality) using a high-density marker map and meiotic mapping. This will narrow the interval and facilitate candidate gene identification. (2) Find and prioritize candidate genes and SNPs within the Hrtfm4 interval in mice, and then identify SNPs in the human orthologues. (3) Perform association studies of candidate gene polymorphisms in human heart disease patients to look for correlations between genotype and heart disease phenotype. Identification of modifier genes contributing to heart failure can lead to improved diagnostic and therapeutic strategies. [unreadable] [unreadable]